Vittoria Battaglia

Medical Herbalist MCPP, MNIMH.

i. Microbiome: Pro, Pre, Post.., & Phytobiotics for Sleep?

Sleep Medicine..?

The Microbiome-Gut-Brain Connection.

There are trillions of microbial cells as bacteria within the human gastrointestinal system. Here, their role is in the production of the bioactive molecules, substances and metabolites that can then support the physiological processes and systems within the body. The vital functions of these gastrointestinal microbiota, have metabolic capacity even as such of that of the liver, and referred to as a ‘metabolic organ’ itself 1.

The importance of strengthening the gut microbiota in order to improve our digestion of food., or for our general health through regulation of the entero-endocrine signalling pathways, may not be a new concept. More recently, we have become more aware of its role for our immune system.  

However., the gut bacteria also provide communication with central nervous system (CNS) through the metabolic compounds that are produced here., like signals., such as short-chain fatty Acids (SCFA’s), norepinephrine (NE), tryptophan, bile acids, glutamate (Glu), dopamine (DA), histamine and γ-Aminobutyric acid (GABA). These compounds, metabolites or neurotransmitters, each have neuroactive as well as immunomodulatory properties, and are able to affect behaviours and human brain function. As such., sleep-promoting GABA and 5-HT, melatonin., and the wakefulness-promoting histamine, dopamine, epinephrine, cortisol, orexin, and acetylcholine. We have long found from research, that there is significant association between insomnia; the sleep related conditions., and anxiety, stress and depression 2.  

The gastrointestinal system and the brain communicate via these signals, with receptors at other organs such as pancreas, liver and oesophagus. Through fibres of the afferent vagus nerve., these signal through to the microbiota at the gut, from up to 500 million neurons at the gut wall submucosa., and enteric nervous system [ENS]. There are more neurons produced at the ENS than at the spine, whilst over 30 neurotransmitters in total are produced 3. 

This two-way relationship of connected sympathetic and vagus nerve system, are what now constitutes the microbiome-gut-brain axis (MGBA) 4. It includes, the autonomic, the hypothalamus and pituitary axis (HPA) and the spinal cord within it, and it represents the important links between nutrition and gut health; the modulation of the physiological homeostasis., and connecting with the cognitive and emotional brain areas with peripheral GIT functions. As well as being a promising mechanism in which to strengthen and improve health through resiliency., this provides implication for inflammatory and neurological disease as well as therapeutic targets for mood and anxiety disorders, depression and PTSD 5.

The gut microbiota are not only able to affect the synthesising and the life span of neurotransmitters, but they also control the development, renewal and modulation of the neurons of the ENS 6. 

Gastrointestinal neurons have many receptors interacting with hormones and peptides. These are released from enteroendocrine cells (EEC) having a significant role in the homeostasis of the gut. They are the sensory cells that regulate secretions., amongst which are 5-HT, cholecystokinin (CCK), neuropeptide Y (NPY) and ghrelin 7.

CCK production may be stimulated by a protein rich-diet, and levels can remain high for up to 6-hours after a meal. Raised CCK levels increase anxiety 8. NYP on the other hand is released during fasting in response to activation by ghrelin 9. Secretion of NYP, with other neurotransmitters GABA and glutamate., takes place in the brain and spinal cord, and functions not only to maintain energy storage in fats and appetite, but also lowers stress, pain, anxiety, reduces blood pressure and regulates sleeping patterns 10, 11.  

The entero-endocrine signalling., as well as immune responses, are maintained under intricate control, to provide the core population of beneficial bacteria that we know to characterise eubiosis or the balanced and healthy gastrointestinal tract (GIT).  A state of dysbiosis then, will occur when this becomes unbalanced, resulting in increased endotoxin levels, that in severe cases can lead to neurodegeneration if disrupting the intestinal-blood-brain barrier functioning 12, 13.

Clinical studies have found that there is an association between dysbiosis at the gut, and anxiety, depression and stress 14, leading to further suggestion that the processes which we know to regulate sleep., [including that of those metabolites produced, clock gene expression, immune responses, neural and endocrine pathways that influence the sleep], are at both circadian as well as homeostatic level., suggesting then that they can therefore., be influenced by the gut microbiome. 

Many bacterial species have been found to have the ability to produce neurotransmitters themselves, and through SCFA’s are able to affect neurotransmitter release 15. In this case, the SCFA’s that are produced by the GIT microbes., promote the production of anti-inflammatory cytokines and T-Cell differentiation, whilst suppressing pro-inflammatory cytokines being produced 16. These circadian regulated physiological responses might be of interest to targeting the synchronicity of clock genes., as studies have shown that both SCFA’s and secondary bile acids, are both found to increase the gene expression 16.

Cytokines such as IL-1β, IL-18 and TNFα, that are released as part of an immune response, actually inhibit wakefulness-promoting neurons. However., increased levels of cortisol, a glucocorticoid hormone released from the adrenal cortex often in stress response, is shown to promote wakefulness, and is able to even suppress cytokines 17. 

This creates the enquiry for the huge potential of pre-, pro-, and postbiotic treatments, that may help to improve the onset, quality and latency of sleep by targeting the microbiome, or health of the gastrointestinal system.

Part II Part III

References

  1. Vernocchi, P., Del. Chierico, L.  & Putignani, L. (2020) Gut microbiota metabolism and interaction with food components. Int. J. Mol. Sci. 21 (10). 3688.
  2. Alvaro, P. K., Roberts, R. M. & Harris, J. (2013) A systematic review assessing bidirectionality between sleep disturbances, anxiety and depression. Sleep 36: 1059-1068. 
  3. Geng, Z. H., Zhu, Y., Li, Q. L., Zhao, C., Zhou, P. H. (2022) Enteric Nervous System: The Bridge Between the Gut Microbiota and Neurological Disorders. Front Aging Neurosci. 2022 Apr 19; 14:810483.
  4. Cryan, J. F. & Dinan, T. G. (2012) Mind-altering Microorganisms: the impact of the gut microbiota on brain behaviour. Nature Reviews NeuroSci 13:701-712.
  5. Leclercq, S., Forsyth, P., Bienenstock, J. (2016) Post-traumatic stress disorder: does the gut microbiome hold the key? Can J Psychiatry 61:204-13. 
  6. Evrensel, A., Ceylan, M. E. (2015) The gut-brain axis: The missing link in depression. Clin Psychopharmacol neurosci 13:239-44.
  7. Gribble, F. M., Reiman, F. (2016) Enteroendocrine Cells, Chemosensors in the epithelia. Annu Rev Physiol 78, 277-199
  8. Gwak, M-G. & Chang, S-Y. (2021) Gut-brain connection: microbiome, gut barrier and environmental sensors. Immune netw. 21, e20.
  9. Howick, K., Cryan, J.F., et al. (2017) From belly to brain: targeting the ghrelin receptor in appetite and food intake regulation. Int. J. Mol. Sci. 18, 273.
  10. Robinson, S.L., & Thiele, T.E (2017) The role of neuropeptide Y (NPY) in alcohol and drug abuse disorders. Int. Rev. Neurobiol. 136. 177-197.
  11. Tatemoto, K. (2004) Neuropeptide Y: History and overview. Neuropept. Y relat. Pept, 162, 1-21.
  12. Willyard, C. (2021) How gut bacteria alter the brain. Nature 2021, 590, 22-25.
  13. Brown, G. C. (2019) The Endotoxin hypothesis of neurodegeneration. J. Neuroinflammation 2019, 16, 180. 
  14. Easson, C., Lyle, S. M., et al. (2019) Gut microbiome diversity is associated with sleep physiology in humans. PLoSONE 14:0222394. 
  15. Arpaia, N., Campbell, C., Fan, X., et al. (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504: 451-455. 
  16. Govindarajan, K., MacSharry, J., Shanahan, F. et al. (2016) Unconjugated bile acids influence expression of circadian genes: a potential mechanism for microbe-host cross-talk. PLoSONE 11:  e0167319.
  17. Galland, L. (2014) The Gut Microbiome and the Brain.  Journal of Medicinal Food 17: 1261-1272.

Originally published: 02/11/2023
This article was recently reviewed by author for accuracy and updated on 7th October 2026, to include the latest information and taxonomy.

Whilst every care is taken to ensure accurate, reputable and the most recent sources and research for this information, this content is not intended as substitute for advice or treatment from a professional clinician. As with conventional medicines, herbal and natural medicines have active ingredients and can have potent effects and interactions with the body, medications, and with other conditions. Especially for those who are taking prescription or over-the-counter medications, it is advised to consult a professional herbalist or medical doctor before beginning any herbal, supplement or lifestyle program. Care and responsible administration is always strongly advocated.

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